DNA double-strand breaks: Their production, recognition, and repair in eukaryotes

Ohnishi, Takeo; Mori, Eiichiro; Takahashi, Akio

doi:10.1016/j.mrfmmm.2009.06.010

Cited by 88 publications

(73 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although DSBs cause cell death or genomic instability, 2,3) they can be repaired by mechanisms such as non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ rejoins the DNA ends without requiring sequence homologies, and is mediated by a DNA-dependent protein kinase holoenzyme.…”

mentioning

confidence: 99%

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

Nishino

Tanamachi

Nakanishi

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Radiosensitizers are used in cancer therapy to increase the γ-irradiation susceptibility of cancer cells, including radioresistant hypoxic cancer cells within solid tumors, so that radiotherapy can be applied at doses sufficiently low to minimize damage to adjacent normal tissues. Radiation-induced DNA damage is repaired by multiple repair systems, and therefore these systems are potential targets for radiosensitizers. We recently reported that the transient receptor potential vanilloid type 1 (TRPV1) channel is involved in early responses to DNA damage after γ-irradiation of human lung adenocarcinoma A549 cells. Therefore, we hypothesized that TRPV1 channel inhibitors would have a radiosensitizing effect by blocking repair of radiation-induced cell damage. Here, we show that pretreatment of A549 cells with the TRPV1 channel inhibitors capsazepine, AMG9810, SB366791 and BCTC suppressed the γ-ray-induced activation of early DNA damage responses, i.e., activation of the protein kinase ataxia-telangiectasia mutated (ATM) and accumulation of p53-binding protein 1 (53BP1). Further, the decrease of survival fraction at one week after γ-irradiation (2.0 Gy) was enhanced by pretreatment of cells with these inhibitors. On the other hand, inhibitor pretreatment did not affect cell viability, the number of apoptotic or necrotic cells, or DNA synthesis at 24 h after irradiation. These results suggest that inhibition of DNA repair by TRPV1 channel inhibitors in irradiated A549 cells caused gradual loss of proliferative ability, rather than acute facilitation of apoptosis or necrosis. TRPV1 channel inhibitors could be novel candidates for radiosensitizers to improve the efficacy of radiation therapy, either alone or in combination with other types of radiosensitizers. Key words γ-ray; radiosensitizer; transient receptor potential vanilloid type 1 channelRadiation therapy plays an important role in treatment of numerous cancers, 1) because ionizing radiation induces potentially lethal DNA damage, such as DNA double-strand breaks (DSBs). Although DSBs cause cell death or genomic instability, 2,3) they can be repaired by mechanisms such as non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ rejoins the DNA ends without requiring sequence homologies, and is mediated by a DNA-dependent protein kinase holoenzyme. On the other hand, HR processes use undamaged homologous DNA sequences (sister chromatid or the homologous chromosome) to ensure the fidelity of the repair process. [4][5][6] The DNA damage response pathways protect genomic integrity and act as a barrier against cancer, 7) and are important for recovery of irradiated normal cells. However, overexpression of DNA repair proteins is involved in radioresistance of cancer cells, [8][9][10] and therefore these mechanisms also decrease the efficiency of radiation therapy.Since ionizing radiation does not discriminate between cancer cells and normal cells, damage to normal tissues is usually a dose-limiting factor in radiation therapy. In addition, many solid ...

show abstract

mentioning

confidence: 99%

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

Nishino

Tanamachi

Nakanishi

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…Cells likely devote significant resources to the repair of DSBs, as defects in their repair lead to elevated cancer risk and phenotypes resembling accelerated aging (Engels et al 2007). There is a fair degree of flexibility in DSB repair processes (Ohnishi et al 2009). Importantly, the different DSB repair pathways may be associated with different costs and they confer varying levels of risk for inducing mutations at the repair site.…”

mentioning

confidence: 99%

DNA Repair Pathway Choice Is Influenced by the Health of Drosophila melanogaster

Wang

Agrawal

2012

Genetics

View full text Add to dashboard Cite

In nature, individuals vary tremendously in condition and this may be an important source of variation in mutation rate. Condition is likely to affect cell state and thereby impact the amount of DNA damage sustained and/or the way it is repaired. Here, we focus on DNA repair. If low-condition individuals are less capable of devoting the same level of resources to accurate repair, they may suffer higher mutation rates. However, repair decisions are also governed by various aspects of cell physiology, which may render the prediction that "higher-condition individuals use better repair mechanisms" too simplistic. We use a larval diet manipulation in Drosophila melanogaster to create high-and low-condition individuals and then contrast their relative usage of three repair pathways [homologous recombination (HR), single-strand annealing (SSA), and nonhomologous end joining (NHEJ)] that differ in their mechanistic requirements and their mutational consequences. We find that low-condition flies are more likely than high-condition flies to use the most conservative of these three repair pathways, suggesting that physiological constraints on repair pathway usage may be more important than energetic costs. We also show that the repair differences between high-and low-condition flies resemble those between young and old flies, suggesting the underlying mechanisms may be similar. Finally, we observe that the effect of larval diet on adult repair increases as flies age, indicating that developmental differences early in life can have long-lasting consequences.

show abstract

“…In order to survive and function under adverse conditions, it is necessary to repair or eliminate DNA damage, and as a consequence, cells have developed a number of complex repair systems to enable their survival and functioning. Knowledge and understanding of these complex systems will make contributions to biology and medicine (Ohnishi, Mori et al 2009). A recent series of findings established a connection between apoptosis, HR regulation and tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%